In eukaryotic cells, messenger RNAs are extensively processed and or modified both co- and post-transcriptionally. For example, the production of a mature mRNA requires addition of a 5'-methyl guanine cap, splicing out of introns, and coupled 3'-end cleavage/polyadenylation. These maturation steps, which must occur with precise accuracy to produce mature mRNA that can exit the nucleus and interface with the translation machinery in the cytoplasm, are mediated by numerous RNA binding proteins. mRNA maturation is essential for gene expression and hence cellular function. Furthermore, consistent with the critical importance of RNA maturation for proper cellular function, there are numerous examples where human disease is linked to alterations in the mRNA maturation/processing machinery or the cellular machinery that monitors the accuracy of these events. In fact, the major question that underlies quality control of any class of RNA is how cells distinguish properly processed RNAs from those that are incorrectly processed. Our long-term goal is to understand how the cell monitors mRNA export from the nucleus and how this process impacts human disease. This long-term goal will be addressed here by testing the hypothesis that mRNA binding proteins interact with cellular surveillance machinery to assure that properly processed mature mRNAs are preferentially exported to the cytoplasm. Four independent but complementary specific aims are proposed. Aim 1 seeks to understand how a novel class of zinc finger polyadenosine RNA binding proteins recognizes mature mRNA. Aim 2 is designed to understand how associated mRNA binding proteins target mature mRNAs to the nuclear pore for export. Aim 3 seeks to identify new mechanisms that the cell employs for surveillance of the export process. Finally, Aim 4 investigates how changes in the bound complement of mRNA binding proteins contribute to irreversible export of mRNA transcripts from the nucleus to the cytoplasm. These aims will be accomplished through a combination of yeast genetics, biochemical and biophysical methods, structural biology, and high throughput cell biological approaches. PUBLIC HEALTH RELEVANCE: The goal of this project is to understand how cells move information from the cell nucleus where the genetic material is located to the cytoplasm where that information can be decoded and translated into the proteins that mediate all the cellular functions. We are interested in how cells avoid sending incorrect information, in the form of immature RNA messages, to the cytoplasm to avoid various disease states that can arise.